Febuxostat is a non-purine xanthine oxidase inhibitor known from U.S. Pat. No. 5,614,520. It is chemically designated as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid having the structure as represented by Formula I.

Febuxostat is marketed in the United States under the brand name Uloric® and in Europe under the brand name Adenuric® for the chronic management of hyperuricemia in patients with gout. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidate both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore, reducing production of uric acid.
Processes for the preparation of febuxostat and intermediates thereof are disclosed in U.S. Pat. No. 5,614,520; Japanese Patent Nos. JP 2834971; JP 3202607; JP 2706037, JP 10139770 and JP 3169735.
U.S. Pat. No. 5,614,520 discloses preparation of febuxostat by hydrolysis of its corresponding ester using sodium hydroxide. It has been observed that when hydrolysis is carried out with sodium hydroxide, the cyano moiety also gets hydrolyzed along with ester leading to the generation of amide by-product, a very potential impurity in febuxostat API. The structure of the amide by-product is as shown below:

JP 2834971 describes preparation of febuxostat ester via formylation of a 4-hydroxyphenyl substituted thiazole intermediate in the presence of an organic acid, preferably with trifluoroacetic acid, and JP 3202607 describes preparation of febuxostat ester via formylation of a 4-hydroxyphenyl substituted thiazole intermediate in the presence of polyphosphoric acid. The work-up procedure for the isolation of product is tedious requiring a number of steps.
The processes described in U.S. Pat. No. 5,614,520, JP 2706037, JP 10139770 and JP 3169735 involve the use of toxic metal cyanides for the preparation of febuxostat. The use of metal cyanides is hazardous to health and is not recommended for an industrial scale preparation.
Accordingly, there is a need for a process to synthesize febuxostat that is substantially free of the amide by-product. The process should avoid long work-up procedures and allow easy isolation of final product and also avoid the use of toxic metal cyanides.